Scientists in the U.S. have identified a promising target for treating immune system-related disorders that are associated with mutations in a gene known as GTPase of immunity-associated protein 5 (Gimap5). The researchers, led by the team of Kasper Hoebe, Ph.D., at the Cincinnati Children’s Hospital Research Foundation, used inhibitors of glycogen kinase 3β (GSK3β)—a protein that is regulated by Gimap5—to restore normal immune cell function in vitro in cells taken from a human immune disorder patient with a homozygous Gimap5 gene mutation, and also to prevent colitis and liver damage in a mouse model.
“Our data suggest GSK3 inhibitors will improve T-cell survival and function and may prevent or correct immune-related disorders in people with Gimap5 loss-of-function mutations,” said Dr. Hoebe, Ph.D., who is at the division of immunobiology. “Therapeutically targeting this pathway may be relevant for treating people with Gimap5 mutations linked to autoimmunity in type 1 diabetes (T1D), systemic lupus erythematosus (SLE), or asthma.”
Dr. Hoebe and colleagues report on their findings in Nature Communications, in a paper entitled “Gimap5-Dependent Inactivation of GSK3β Is Required for CD4+ T Cell Homeostasis and Prevention of Immune Pathology.”
Gimap proteins are expressed predominantly in lymphocytes, and they act to regulate lymphocyte survival during development, selection, and homeostasis, the authors explain. In particular, Gimap5 has been associated with (auto)immune disease. Polymorphisms in the gene’s protein have been linked with an increased risk of islet autoimmunity in T1D, SLE, and asthma. Model rodents that have a complete loss of function (LOF) Gimap5 gene demonstrate reduced lymphocyte survival, loss of immunological tolerance, and a predisposition to autoimmunity. These animals also spontaneously develop lethal colitis.
Despite the critical role of Gimap5 in immune cell function, the mechanism(s) underlying its activity haven’t yet been identified. The Cincinnati team has now shown that Gimap5 is a critical inhibitor of GSK3β in both human and mouse CD4+ cells. If GSK3 isn't inactivated—due to lack of Gimap5 function—it causes DNA damage in expanding T cells, which affects T-cell function and survival. The researchers’ studies showed that targeting GSK3β in the T cells of Gimap5-deficient mice led to improved T-cell survival, prevented liver damage and the development of colitis.
The team also identified a 16-year-old human patient with lymphopenia, who carried a rare, homozygous Gimap5 mutation that resulted in a complete lack of Gimap5 protein. The patient’s immunodeficiency was “strikingly similar” to Gimap5-deficient mice, the authors write, including increased DNA damage and reduced T-cell survival upon T-cell activation. Treating the patient’s T cells in vitro using a GSK3β inhibitor restored normal function and survival.
T cells depend on their ability to undergo clonal expansion for an efficient immune response during infection or to maintain immune homeostasis in the gut, the researchers state. “Our studies reveal a key role for Gimap5 in inactivating GSK3β during CD4+ T cell activation, a link that is critically required to maintain T cell fitness and allows for productive T cell proliferation. We propose that the Gimap5- mediated inactivation of GSK3β is an essential molecular mechanism to support productive CD4+ T cell responses.” They claim that their results point to a “remarkable therapeutic potential” for the use of GSK3 inhibitors to improve CD4+ T-cell survival and proliferation and to prevent immunopathology.
GSK3 inhibitors have already been used to treat disease, including Alzheimer’s disease, mood disorder, cancer, and diabetes mellitis, they note. “Our current data reveal a new therapeutic application of GSK3 inhibitors specifically in the treatment of immunodeficient patients that have GIMAP5 LOF [loss of function] mutations.…We posit that GSK3-inhibitors will improve overall T-cell survival and function and may prevent/correct immune- associated sequelae observed in these patients.”
The researchers acknowledge that further research will be needed before their findings can be translated into the clinic. Nevertheless, Hoebe says, “We believe the use of GSK3 inhibitors to prevent or correct these type of immune-related diseases holds great potential.”
The reearchers are now investigating the relationship between Gimap5 mutations and GSK3 regulation on T-cell malfunction in patients with immune disorders. Work is also ongoing to evaluate the therapeutic potential of GSK3 inhibitors in preclinical mouse models of allergic lung disease and lupus.